. Dr. Cheng proposes to study the biochemical pharmacology of anti-HIV nucleosides. The project aims to clarify key cellular biochemical determinants that play a key role in the action, resistance, and toxicity of anti-HIV nucleoside analogs. The proposed two specific aims are: (1) Purification and characterization of a cytoplasmic DNA exonuclease that may constitute a major mechanism of viral resistance to anti-HIV 1 nucleoside analogs; (2) Isolation and characterization of mitochondrial deoxynucleoside triphosphate (dNTP) carrier that may be a significant determinant in the toxicity of anti-HIV-1 nucleoside analogs to mitochondrial function. The investigator believes that the proposed studies should be useful in better understanding the pharmacology of anti-HIV- 1 analogs, new drug discovery, and the improvement of therapy with currently approved nucleoside analogs.